The Role of ER Stress and the Unfolded Protein Response in Obesity Associated Type 2 Diabetes

Pancreatic β-cell dysfunction plays a central role in the pathogenesis of type 2 diabetes. This dysfunction is characterised by secretory defects in the β-cells and the loss of β-cell mass, at least in part secondary to increased β-cell apoptosis. Although the mechanisms through which β-cell dysfunction develops are unclear, accumulating evidence suggests that elevated levels of circulating free fatty acids (FFAs) as can occur under conditions of obesity, play a role in the pathogenesis of type 2 diabetes. It has been suggested that endoplasmic reticulum (ER) stress and the resulting unfolded protein response (UPR) play a role in FFA induced β-cell dysfunction. This thesis was aimed at investigating the role of obesity induced ER stress in the development of β-cell dysfunction in type 2 diabetes. The UPR was induced in MIN6 β-cells in response to both the saturated fatty acid (FA) palmitate, and unsaturated fatty acid oleate. Palmitate however induced a more marked ER stress response in comparison to oleate. Although both FAs induced ER stress, only palmitate evoked apoptosis in the β-cells, indicative of the differential signalling by unsaturated and saturated fatty acids. ER stress and evidence of functional adaptation was also observed in islets obtained from Zucker and Zucker diabetic fatty (ZDF) rodent models of obesity. The development of β-cell dysfunction in the progression from obesity to obesity associated type 2 diabetes in the ZDF rats was however not accompanied by a further increase in ER stress markers. This suggests that ER stress signalling does not play a significant role in the development of β-cell dysfunction. In conclusion, the studies outlined in this thesis demonstrate that ER stress is induced in in vitro and in vivo models of β-cell lipotoxicity. It is however apparent, that ER stress does not contribute significantly to β-cell dysfunction and perhaps, only plays a small insignificant role in β-cell apoptosis in the pathogenesis of type 2 diabetes. It is hypothesised, that β-cell dysfunction develops in type 2 diabetes as a result of the inability of the β-cell to mount an additive UPR in response to ER stress.